Compared with conventional modes of patient-initiated mechanical ventilation, respiratory mechanical unloading aims at improving the match between ventilator pressure profiles and the specific derangements in lung mechanics. This may reduce lung barotrauma. The ventilator pressure increases either in proportion to the volume or to the flow of spontaneous breathing (elastic or resistive unloading), thereby selectively decreasing elastic or resistive work of breathing. The clinician sets a gain of increase in pressure per unit of volume or flow. In an attempt to develop criteria for selecting an appropriate gain, we investigated the effects of unloading using increasing gains that either partially compensated or overcompensated lung elastance or resistance. We studied spontaneously breathing, anesthetized, and tracheotomized rabbits. Compared with continuous positive airway pressure, respiratory unloading decreased the electromyographic activity of the diaphragm and increased minute ventilation in normal (n = 5) and surfactant-depleted (n = 6) animals when the gain was partially compensating. Fluctuations in systemic blood pressure associated with breathing decreased. The end-expiratory lung volume remained unchanged. Overcompensation of lung elastic recoil during elastic unloading with an excessive gain caused large tidal volumes associated with a cyclic decrease in blood pressure. Overcompensation of resistance induced oscillations. Complete inhibition of spontaneous breathing occurred with a further increase in gain. We conclude that respiratory unloading with an appropriate gain enhances the effect of diaphragmatic muscle activity on ventilation. A stable breathing pattern ensues whenever a regular spontaneous effort is present. However, excessive gain causes large tidal volumes during elastic unloading or oscillations during resistive unloading.